This invention relates to a novel process for preparing unsymmetrical dithioacetals and dithioketals from aryl aldehydes and ketones. More particularly, this invention relates to a process for preparing certain 2-substituted quinoline dithiaalkanedioic acids.
Various methods for preparing dithioacetals and dithioketals from aldehyde or ketone precursors are well known in the art, especially where the two thioether moieties are identical or are constituent parts of a cyclic functionality. For example, reaction of thiol or activated thiol reagents with carbonyl-containing or activated carbonyl-containing reagents can yield symmetric and cyclic dithioacetals and dithioketals. Activation by addition of a suitable Lewis acid or a trialkylsilyl halide has been reported. Thus, certain symmetric and cyclic dithioacetals have been prepared by reaction of mercaptans and aldehydes (or corresponding dimethyl acetals) in the presence of boron trifluoride etherate. C. D. Perchonock et al., J. Med. Chem., 29, 1442-1452 (1986). However, preparation of unsymmetric dithioacetals and dithioketals presents special synthetic problems. Using a mixture of two different thiols in the aforementioned reaction produces the unsymmetrical product, but only as one component in a statistical mixture of symmetrical and unsymmetrical products.
One method for preparing unsymmetrical dithioacetals and dithioketals involves modifying existing symmetrical dithioacetals and dithioketals, e.g., copending U.S. patent application Ser. No. 011,181, filed Feb. 5, 1987. Since selective modification of only one of the two identical thioether moieties would rarely be efficient, one would expect this method to have only limited applicability.
Selective methods for preparing hemithioacetals have been reported. For example, reactions of various aldehydes and ketones with alkyl- and arylthiosilanes of the formula RSSi(CH.sub.3).sub.3 have been reported to yield, depending upon the specific conditions used, O-silylhemithioacetals and ketals of ##STR1## or dithioacetals and dithioketals of Formula B ##STR2## wherein R is inter alia alkyl, alkylene (forming a cyclic dithioketal), or other saturated or unsaturated hydrocarbon species; and wherein for aldehydes one of R' and R" is hydrogen and the other is inter alia alkyl or other saturated or unsaturated hydrocarbon species, and for ketones R' and R" are independently inter alia alkyl, alkylene (derived from cyclic ketones), or other saturated or unsaturated hydrocarbon species. D. A. Evans et al., J. Am. Chem. Soc., 99, 5009-5017 (1977). However, no practical method has been reported for selective preparation of unsymmetrical dithioacetals. For example, the method described by Evans has not been found useful for the preparation of the 2-substituted quinoline dithiaalkanedioic acids described in this invention.
A method described in copending U.S. patent application Ser. No. 011,166, filed Feb. 5, 1987, for preparing chiral unsymmetrical dithioacetals involves acid-catalyzed reaction of aldehydes with a mixture of thiols of the formula HSR" and thioic S-acids of the formula HSC(0)R.sup.4 to yield compounds of Formula C (as one component in a statistical distribution of components) ##STR3## wherein R.sup.a and R.sup.b can be various substituents, including inter alia hydrogen and 2-substituted quinoline moieties; R" can be various substituents, including inter alia alkyl and carboxyalkyl; and R.sup.4 can be chiral or achiral alkyl or optionally substituted aryl. Base hydrolysis of the S-acyl group of compounds of Formula C followed by alkylation of the resultant free thiol group yields dithioacetals of Formula D ##STR4## wherein R.sup.a, R.sup.b, R', and R.sup.4 are defined as above and R' can be various substituents, including inter alia alkyl and carboxyalkyl. Although the method described in U.S. Ser. No. 011,166 can be used to prepare compounds described in the present invention, the methods are distinguishable by the differing reagents and conditions used and in the differing intermediates produced.
The present invention provides a particularly advantageous two-step method for preparing unsymmetrical dithioacetals and dithioketals from aryl aldehydes and ketones.